This RDCRC proposal focuses on three relatively rare vascular malformations that are poorly understood in terms of biological mechanisms, are resource-intensive to manage effectively, and have high probability of serious neurological morbidity. Each disease is characterized by the development of a distinct category of vascular malformations and a unique spectrum of clinical and phenotypic outcomes, for which biological risk factors are either poorly understood or completely unknown. The identification of such risk factors that relate to disease progression would be of immediate significance for patient surveillance and for optimizing management. Further, although there are no specific medical therapies for these diseases, appropriate treatment (efficacy) trials will require risk stratification for selection and surrogate outcomes for trial development. The general effort is focused on the establishment of research grade, relational, scalable clinical databases to conduct observational studies or interventional trials. Further, we will identify novel markers for disease progression. The combined effort will foster new approaches to the diagnosis, prevention, and treatment of these three rare diseases, providing novel means of risk stratification that will be applicable to future clinical trials. The three projects synergize with one another in these common goals and objectives, in their use of common infrastructure elements, and in overlapping but complementary expertises of the investigators. Project 1 is focused on studying cerebral cavernous malformations (CCMs), which are clusters of abnormally enlarged blood vessels occurring in the brain and spinal cord. CCMs are a cause of neurological morbidity, the most feared of which is intracranial hemorrhage and acute neurological events or death, but also includes seizures and chronic neurological disability. The vascular dysplasia appears to be at the capillary level and lesions are low-flow without shunting of blood. There are three known familial forms, all with autosomal dominant inheritance, in addition to a sporadic form, with each type representing a somewhat distinct rare disease entity with a different phenotype. We will be studying a heritable form of the disease seen in Hispanic families of the Southwest, which is caused by the Common Hispanic Mutation (CCM1-CHM) and has an estimated population prevalence of 15/100,000. Aim 1 will establish a CCM type 1 common Hispanic mutation (CCM1-CHM) database/Registry at the University of New Mexico (UNM). Design of the database will be in consultation with Angioma Alliance (to ensure compatibility with their existing registry) and be implemented by collaboration with the Genetics and Statistical Analysis Core of this RDCRC and the DMCC. It will be relational and scalable for use in future observational studies and interventional trials. We will recruit 500 familial CCM1-CHM patients and collect detailed clinical and imaging data, as well as DMA samples. Aim 2 capitalizes on this unique cohort of CCM1 patients with an identical mutation to investigate additional genetic variation as a possible explanation for the wide range of clinical variability seen in this disease with lesion burden, as a surrogate for adverse outcomes, as the primary outcome. The longitudinal component in Aim 3 will collect natural history data together with detailed imaging evaluations, allowing us to examine disease progression over the study period as measured by increase in lesion burden. The infrastructure of the overall grant and creative collaborations will foster an improved understanding of risk factors for intracranial hemorrhage in CCM. It will prepare all groups for future clinical studies for agents to prevent lesion growth, hemorrhage or the neurological deficits caused by hemorrhage. Some of these discoveries may be applicable to other familial forms of CCM, as well as sporadic forms. The large amount of data acquired and analyzed will be of value to all CCM researchers, and serve as a potential model for studying larger cohorts of this disease in New Mexico and elsewhere.